Kim Beom Su, Kang Hyo-Jin, Park Ji-Yun, Lee Jun
1] Wonkwang Bone Regeneration Research Institute, Wonkwang University, Iksan, Korea [2] Research and Development Department, Bonecell Biotech Inc., Daejeon, Korea.
Wonkwang Bone Regeneration Research Institute, Wonkwang University, Iksan, Korea.
Exp Mol Med. 2015 Jan 9;47(1):e128. doi: 10.1038/emm.2014.95.
Fucoidan has attracted attention as a potential drug because of its biological activities, which include osteogenesis. However, the molecular mechanisms involved in the osteogenic activity of fucoidan in human alveolar bone marrow-derived mesenchymal stem cells (hABM-MSCs) remain largely unknown. We investigated the action of fucoidan on osteoblast differentiation in hABM-MSCs and its impact on signaling pathways. Its effect on proliferation was determined using the crystal violet staining assay. Osteoblast differentiation was evaluated based on alkaline phosphatase (ALP) activity and the mRNA expression of multiple osteoblast markers. Calcium accumulation was determined by Alizarin red S staining. We found that fucoidan induced hABM-MSC proliferation. It also significantly increased ALP activity, calcium accumulation and the expression of osteoblast-specific genes, such as ALP, runt-related transcription factor 2, type I collagen-α 1 and osteocalcin. Moreover, fucoidan induced the expression of bone morphogenetic protein 2 (BMP2) and stimulated the activation of extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase by increasing phosphorylation. However, the effect of fucoidan on osteogenic differentiation was inhibited by specific inhibitors of ERK (PD98059) and JNK (SP600125) but not p38 (SB203580). Fucoidan enhanced BMP2 expression and Smad 1/5/8, ERK and JNK phosphorylation. Moreover, the effect of fucoidan on osteoblast differentiation was diminished by BMP2 knockdown. These results indicate that fucoidan induces osteoblast differentiation through BMP2-Smad 1/5/8 signaling by activating ERK and JNK, elucidating the molecular basis of the osteogenic effects of fucoidan in hABM-MSCs.
岩藻依聚糖因其包括成骨作用在内的生物活性而作为一种潜在药物受到关注。然而，岩藻依聚糖在人牙槽骨髓间充质干细胞（hABM-MSCs）中成骨活性所涉及的分子机制仍 largely 未知。我们研究了岩藻依聚糖对 hABM-MSCs 中破骨细胞分化的作用及其对信号通路的影响。使用结晶紫染色法测定其对增殖的影响。基于碱性磷酸酶（ALP）活性和多种成骨细胞标志物的 mRNA 表达评估成骨细胞分化。通过茜素红 S 染色测定钙积累。我们发现岩藻依聚糖诱导 hABM-MSC 增殖。它还显著增加 ALP 活性、钙积累以及成骨细胞特异性基因如 ALP、 runt 相关转录因子 2、I 型胶原-α1 和骨钙素的表达。此外，岩藻依聚糖诱导骨形态发生蛋白 2（BMP2）的表达，并通过增加磷酸化刺激细胞外信号相关激酶（ERK）、c-Jun N 端激酶（JNK）和 p38 丝裂原活化蛋白激酶的激活。然而，岩藻依聚糖对成骨分化的作用被 ERK（PD98059）和 JNK（SP600125）的特异性抑制剂抑制，但未被 p38（SB203580）抑制。岩藻依聚糖增强 BMP2 表达和 Smad 1/5/8、ERK 和 JNK 磷酸化。此外，BMP2 敲低减弱了岩藻依聚糖对成骨细胞分化的作用。这些结果表明岩藻依聚糖通过激活 ERK 和 JNK 经由 BMP2-Smad 1/5/8 信号传导诱导成骨细胞分化，阐明了岩藻依聚糖在 hABM-MSCs 中成骨作用的分子基础。
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